7UC7

Stat5a Core in complex with Compound 17

Summary for 7UC7

• Entry DOI: 10.2210/pdb7uc7/pdb
• Descriptor: Signal transducer and activator of transcription 5A, GLYCEROL, N-{5-[difluoro(phosphono)methyl]-1-benzothiophene-2-carbonyl}-3-methyl-L-valyl-L-prolyl-N~3~-(1-benzofuran-5-yl)-N,N-dimethyl-beta-alaninamide, ... (4 entities in total)
• Functional Keywords: stat5a, activator, transcription, transcription-inhibitor complex, transcription/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 66653.56

Authors

Meagher, J.L.,Stuckey, J.A. (deposition date: 2022-03-16, release date: 2023-02-15, Last modification date: 2024-04-03)

Primary citation

Kaneshige, A.,Bai, L.,Wang, M.,McEachern, D.,Meagher, J.L.,Xu, R.,Kirchhoff, P.D.,Wen, B.,Sun, D.,Stuckey, J.A.,Wang, S.
Discovery of a Potent and Selective STAT5 PROTAC Degrader with Strong Antitumor Activity In Vivo in Acute Myeloid Leukemia.
J.Med.Chem., 66:2717-2743, 2023

PubMed Abstract: STAT5 is an attractive therapeutic target for human cancers. We report herein the discovery of a potent and selective STAT5 degrader with strong antitumor activity . We first obtained small-molecule ligands with sub-micromolar to low micromolar binding affinities to STAT5 and STAT6 SH2 domains and determined co-crystal structures of three such ligands in complex with STAT5A. We successfully transformed these ligands into potent and selective STAT5 degraders using the PROTAC technology with AK-2292 as the best compound. AK-2292 effectively induces degradation of STAT5A, STAT5B, and phosphorylated STAT5 proteins in a concentration- and time-dependent manner in acute myeloid leukemia (AML) cell lines and demonstrates excellent degradation selectivity for STAT5 over all other STAT members. It exerts potent and specific cell growth inhibitory activity in AML cell lines with high levels of phosphorylated STAT5. AK-2292 effectively reduces STAT5 protein and achieves strong antitumor activity in mice at well-tolerated dose schedules.

PubMed: 36735833
DOI: 10.1021/acs.jmedchem.2c01665

Experimental method

X-RAY DIFFRACTION (3.102 Å)